Identifying Novel SUMO Regulators of TGF Beta-induced EMT and Breast Cancer Invasion

Simple item page
atmire.migration.oldid4410
dc.contributor.advisorBonni, Shirin
dc.contributor.authorChandhoke, Amrita Singh
dc.contributor.committeememberJirik, Frank
dc.contributor.committeememberChan, Jennifer
dc.contributor.committeememberArcellana-Panlilio, Mayi
dc.contributor.committeememberLai, Raymond
dc.date.accessioned2016-05-06T18:35:49Z
dc.date.available2016-05-06T18:35:49Z
dc.date.issued2016
dc.date.submitted2016en
dc.description.abstractEpithelial-mesenchymal transition (EMT) is a fundamental developmental process, which is reactivated in cancer contributing to tumor invasiveness and metastasis. The secreted factor transforming growth factor β (TGFβ) is a potent inducer of EMT in development and cancer. The transcriptional regulator SnoN and E3 ubiquitin ligase Smurf2 control TGFβ signalling in a complex manner with implications for cancer development and progression. The focus of my doctoral studies has been to examine the nature and regulation of SnoN and Smurf2 functions in TGFβ-induced EMT. In this regard, I have characterized the role of SUMO pathway in modifying both SnoN and Smurf2, thereby regulating their roles in controlling EMT. I employed three-dimensional (3D) model systems to follow EMT in mammary epithelial cells and invasive growth behavior of breast cancer cells to increase the chance of getting results with in-vivo relevance. My studies have led to the identification of the protein TIF1γ as a novel SUMO E3 ligase that promotes SnoN sumoylation. Importantly, my data show that TIF1γ acts via SnoN sumoylation to suppress TGFβ-induced EMT in 3D-mammary epithelial cell-derived acini. Next, I found that Smurf2 suppresses EMT in 3D cultures of epithelial cells. Also, I discovered that the SUMO pathway modifies Smurf2 at specific lysine residues through the SUMO E3 ligase PIAS3. Importantly, my data suggest that sumoylation is critical for Smurf2 to suppress TGFβ-induced EMT. Mechanistically, I found that sumoylation promotes Smurf2-induced degradation of TGFβ receptors, leading to suppression of TGFβ signalling and EMT. Lastly, my latest findings suggest that the PIAS3-Smurf2 sumoylation pathway suppresses TGFβ-induced invasive growth of 3D-breast cancer cell-derived spheroids. Future studies, using a xenograft cancer model will aim to investigate role of the PIAS3-Smurf2 sumoylation pathway in tumorigenesis. Overall, our research questions have led to the identification of novel regulators of TGFβ-induced EMT and potentially breast cancer invasion and metastasis. Importantly, SUMO-based pathways promote the ability of both SnoN and Smurf2 to suppress TGFβ-induced EMT in mammary epithelial cells, with relevance to cancer cell invasion and metastasis. Our findings could help in providing potential new diagnostic or druggable targets for treatment of breast tumors.en_US
dc.identifier.citationChandhoke, A. S. (2016). Identifying Novel SUMO Regulators of TGF Beta-induced EMT and Breast Cancer Invasion (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca. doi:10.11575/PRISM/26433en_US
dc.identifier.doihttp://dx.doi.org/10.11575/PRISM/26433
dc.identifier.urihttp://hdl.handle.net/11023/2992
dc.language.isoeng
dc.publisher.facultyGraduate Studies
dc.publisher.institutionUniversity of Calgaryen
dc.publisher.placeCalgaryen
dc.rightsUniversity of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission.
dc.subjectBiology
dc.subjectBiology--Cell
dc.subjectBiology--Molecular
dc.subjectHuman Development
dc.subjectOncology
dc.subjectBiochemistry
dc.subject.classificationTGF-betaen_US
dc.subject.classificationEMT-epithelial mesenchymal transitionen_US
dc.subject.classificationSUMO- small ubiquitin-like modifieren_US
dc.subject.classificationSmurf2en_US
dc.subject.classificationTIF1gammaen_US
dc.subject.classificationSnoNen_US
dc.subject.classificationTumoren_US
dc.subject.classification3D- three dimensionalen_US
dc.titleIdentifying Novel SUMO Regulators of TGF Beta-induced EMT and Breast Cancer Invasion
dc.typedoctoral thesis
thesis.degree.disciplineBiochemistry and Molecular Biology
thesis.degree.grantorUniversity of Calgary
thesis.degree.nameDoctor of Philosophy (PhD)
ucalgary.item.requestcopytrue
Files
Collections
Open Theses and Dissertations